Design and optimization of N-acylhydrazone pyrimidine derivatives as E. coli PDHc E1 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: He, Haifeng; Xia, Hongying; Xia, Qin; Ren, Yanliang; He, Hongwu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 20(2017)
• Page Start: 5652
• Page End: 5661
• Publication Date: 2017-10-15
• Subjects: ThDP -- E. coli PHDc E1 -- Enzyme-selective -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.08.038
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: N -Acylhydrazone pyrimidineA14 exhibited most powerful inhibitory potency against E. coli PDHc E1 (IC50 = 0.15 µM). Abstract: By targeting the thiamin diphosphate (ThDP) binding site of Escherichia coli ( E. coli ) pyruvate dehydrogenase multienzyme complex E1 (PDHc E1), a series of novel 'open-chain' classes of ThDP analogsA, B, andC with N -acylhydrazone moieties was designed and synthesized to explore their activities against E. coli PHDc E1 in vitro and their inhibitory activity against microbial diseases were further evaluated in vivo . As a result, A1 –23 exhibited moderate to potent inhibitory activities against E. coli PDHc E1 (IC50 = 0.15–23.55 μM). The potent inhibitorsA13, A14, A15, C2, had strong inhibitory activities with IC50 values of 0.60, 0.15, 0.39 and 0.34 μM against E. coli PDHc E1 and with good enzyme-selective inhibition between microorganisms and mammals. Especially, the most powerful inhibitorA14 could 99.37% control Xanthimonas oryzae pv. Oryzae . Furthermore, the binding features of compoundA14 within E. coli PDHc E1 were investigated to provide useful insights for the further construction of new inhibitor by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated thatA14 had most powerful inhibition against E. coli PDHc E1 due to the establishment of stronger interaction with Glu571, Met194, Glu522, Leu264 and Phe602 at active site of E.coli PDHc E1. It could be used as a lead compound for further optimization, and may have potential as a new microbicide.